MESA Core (Core G) ? Project Summary No therapies have proven effective against Alzheimer's disease (AD) dementia. As a result, the field has shifted focus to develop strategies for prevention, early intervention, and the identification of early antecedent biomarkers and risk factors that predict later life vulnerability or resilience to dementia. To address these important scientific goals, an existing cohort of older adults ? well characterized with regard to mid- to later-life metabolic and vascular risk factors ? will be integrated into the Wake Forest ADCC. The Multi-Ethnic Study of Atherosclerosis (MESA) is a multi-site study of subclinical and incident vascular and metabolic disease, and Wake Forest is one of six clinical sites. This partnership between MESA and the ADCC provides a unique opportunity to leverage the longitudinal characterization of MESA participants to complement and expand our Center's theme focused on metabolic and vascular pathogenetic contributions to AD and other related disorders. In 2000, 734 adults, aged 58 to 97 years (46% African-American, 54% non-Hispanic Caucasian), were enrolled into the Wake Forest MESA cohort. Participants have undergone extensive metabolic phenotyping (e.g., fasting glucose, insulin, hemoglobin A1C, lipid particle size, plasma lipidomic and metabolomic analyses); vascular phenotyping (e.g., arterial stiffness, coronary artery calcification, carotid ultrasound); whole genome and exome sequencing and epigenetic characterization; repeated retinal imaging, and a brief cognitive assessment in 2010-2012. The ADCC MESA Core will add clinical and cognitive assessments (Uniform Data Set and supplemental cognitive tests); neuroimaging (MRI, amyloid PET); and collection of CSF and brains. With the support of an NIA-funded ADCC, we will be able to enroll 540 MESA participants within the first 2 years of our award period and repeat assessments 3 years later, as recommended in the P30 RFA to accomplish the following Specific Aims: 1) assess clinical, cognitive, and neurological endpoints in MESA participants to characterize MCI, AD, VCI, and other related disorders, and to facilitate research focused on relationships between cognitive status and antecedent metabolic and vascular risk factors; 2) conduct longitudinal follow-up of MESA Core participants to permit examination of antecedent metabolic and vascular biomarkers that predict cognitive and biomarker trajectories (decline and resilience), incident MCI, and AD/VCI; 3) provide multidimensional data and other resources to foster systems and pathway analyses of genetic, epigenetic, and phenotypic data to identify the metabolic and vascular pathways that predict dementia risk, and elucidate the clinical and pathophysiologic relationships between AD and VCI to inform the development of novel biomarkers and therapeutic targets; and 4) provide resources to facilitate investigations examining the potential impact of race on relationships between metabolic and vascular pathways, cognitive function, and AD/VCI biomarkers.